It is well recognized that despite advances in cardiovascular care, the prevalence of atherosclerosis and its complications, myocardial infarction and stroke, remains the leading cause of morbidity and mortality worldwide. Current noninvasive methods to evaluate the status and assess the effects of therapeutic intervention rely mainly on anatomic and structural features of the lesion. New noninvasive molecular imaging techniques of atherosclerosis1 may enable a novel biologically based approach that exceeds anatomic and morphologic examination of the vessel wall. Current imaging modalities disclose minimal information about this key biological process. Thus, by characterizing the pathophysiological processes responsible for plaque progression and instability using non-invasive and reliable imaging approaches, it may be possible to early identify high-risk patients and to evaluate the effects of interventions, including emerging therapies. The central goal of this work is therefore the study of molecular imaging methods for the non-invasive evaluation of the biological activity associated with atherogenesis. We propose the use of versatile/modular (allowing facile interchange of MR imaging labels and ligands) and well-characterized high-density lipoprotein (HDL) imaging nanocarrier platforms for the targeted (known and newly discovered targets) study of the progression and regression of atherosclerotic plaques in vivo. These spherical HDL platforms will be programmed for single modality imaging (Gd-MR or iron oxide-MR) allowing assessment at possibly different levels of sensitivity (Aim 1). Based on in vivo efficacy imaging studies the lead candidate between the native and synthetic MR-HDL platforms will be selected for further study in the subsequent aims. In vitro and in vivo studies will be linked intimately with the nanocarriers design strategies and assembly work to achieve validation of the biological performance and mechanism of action elucidation of the HDL MR imaging platforms (Aim 2). Known and newly identified targets will be functionalized to achieve plaque specific selective targeting. We will demonstrate the in vivo efficacy of these targeted HDL MR-nanocarriers for the evaluation of plaque progression and regression in mouse and rabbit models of atherosclerosis (Aim 3). PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the main killer worldwide, a pandemic largely driven by the growing prevalence of atherosclerosis. However, atherosclerosis progresses slowly and silently over decades, a prolonged course that represents a window of opportunity for diagnosis before symptoms occur. Thus, novel imaging techniques offer new prospects to detect early stages and identify those individuals with higher risk.